What is the evidence for cholinesterase inhibitors (medicines designed to improve memory and thinking in people with dementia), when used with people who have vascular dementia?
Vascular dementia (or vascular cognitive impairment) is a term used when a person has problems with memory and thinking that are caused by a disruption of blood supply. There are few drug treatments for vascular dementia.
In this review, we evaluated three drugs from the cholinesterase inhibitor family, donepezil, rivastigmine, and galantamine. These medications are widely used in Alzheimer's dementia but may also be useful in people with vascular dementia. Previous reviews of these cholinesterase inhibitor drugs could not draw definitive conclusions for people with vascular dementia.
Purpose of this review
We wanted to learn whether cholinesterase inhibitors benefit people with vascular dementia. We were interested in their effects on memory, thinking, and daily functioning. We wanted to learn of any harms associated with these drugs.
As some time has passed since the previous reviews, we wanted to update them by searching for new studies. We combined the three previous reviews on donepezil, rivastigmine and galantamine into one review.
What we did
We searched for studies that described the effects of donepezil, rivastigmine, and galantamine for people with vascular dementia. We searched databases of scientific studies and contacted drug manufacturers and experts in vascular dementia. Our search is current to 19 August 2020.
To be included in our review, studies had to randomly assign people with vascular dementia to treatment with a cholinesterase inhibitor, or a dummy pill (placebo) and then compare the two groups. Studies comparing one cholinesterase inhibitor against another were also included. We combined the results of the included studies for each medicine to estimate how effective they were and how likely they were to cause side effects. We assessed how well the studies were conducted and how credible the results were.
We did not find studies which compared different cholinesterase inhibitors with each other. To see whether the different cholinesterase inhibitor drugs differed in their effects, we used a technique called network meta-analysis, which can provide an idea of how the medicines might perform if they were compared head-to-head.
What we found
We found 8 studies including a total of 4373 people with vascular dementia (or vascular cognitive impairment). The studies tested the drug donepezil at two different doses (5mg and 10mg daily), against each other and against placebo. Rivastigmine and galantamine were tested against placebo only. Rivastigmine is available as a skin patch, but the studies only tested the pill version. All eight studies evaluated participants when they first started taking the medicine or placebo and again six months later. Different tests were used to measure the effects. All studies included tests of memory, thinking and reported side effects.
People taking donepezil or galantamine had better scores on memory and thinking tests than people taking placebo, but the benefits were modest and may not be large enough to be evident in daily life. There was no evidence of a difference for rivastigmine, but the evidence was less certain, and the doses taken by some participants may have been too low to show an effect. We found evidence that when compared to placebo, side effects such as nausea and diarrhoea, were more common in people taking donepezil 10mg and galantamine, but probably not donepezil 5mg. We were unable to draw conclusions about side effects of rivastigmine from the studies.
No vascular dementia trials comparing the different cholinesterase against each other have been conducted. Using the information from the individual studies, we made indirect assessments of how the drugs would perform if tested head-to-head. The results suggested that donepezil 10 mg had the greatest effect on memory and thinking, but caused more side effects than donepezil 5 mg or galantamine.
There were only a small number of studies for each drug. Certainty in the results varied between drugs and between outcomes, from high to very low certainty. The studies showed only a small benefit at most; however, in the absence of any other treatments, people living with dementia may still wish to consider use of these drugs.
We found moderate- to high-certainty evidence that donepezil 5 mg, donepezil 10 mg, and galantamine have a slight beneficial effect on cognition in people with VCI, although the size of the change is unlikely to be clinically important. Donepezil 10 mg and galantamine 16 to 24 mg are probably associated with more adverse events than placebo. The evidence for rivastigmine was less certain.
The data suggest that donepezil 10 mg has the greatest effect on cognition, but at the cost of adverse effects. The effect is modest, but in the absence of any other treatments, people living with VCI may still wish to consider the use of these agents. Further research into rivastigmine is needed, including the use of transdermal patches.
Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to dementia. There are currently no pharmacological treatments recommended for improving either cognition or function in people with VCI. Three cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are licenced for the treatment of dementia due to Alzheimer's disease. They are thought to work by compensating for reduced cholinergic neurotransmission, which is also a feature of VCI. Through pairwise comparisons with placebo and a network meta-analysis, we sought to determine whether these medications are effective in VCI and whether there are differences between them with regard to efficacy or adverse events.
(1) To assess the efficacy and safety of cholinesterase inhibitors in the treatment of adults with vascular dementia and other VCI.
(2) To compare the effects of different cholinesterase inhibitors on cognition and adverse events, using network meta-analysis.
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 19 August 2020.
We included randomised controlled trials in which donepezil, galantamine, or rivastigmine was compared with placebo or in which the drugs were compared with each other in adults with vascular dementia or other VCI (excluding cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)). We included all drug doses and routes of administration.
Two review authors independently identified eligible trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the certainty of the evidence. The primary outcomes were cognition, clinical global impression, function (performance of activities of daily living), and adverse events. Secondary outcomes were serious adverse events, incidence of development of new dementia, behavioural disturbance, carer burden, institutionalisation, quality of life and death. For the pairwise analyses, we pooled outcome data at similar time points using random-effects methods. We also performed a network meta-analysis using Bayesian methods.
We included eight trials (4373 participants) in the review. Three trials studied donepezil 5 mg or 10 mg daily (n= 2193); three trials studied rivastigmine at a maximum daily dose of 3 to 12 mg (n= 800); and two trials studied galantamine at a maximum daily dose of 16 to 24 mg (n= 1380). The trials included participants with possible or probable vascular dementia or cognitive impairment following stroke. Mean ages were between 72.2 and 73.9 years. All of the trials were at low or unclear risk of bias in all domains, and the evidence ranged from very low to high level of certainty.
For cognition, the results showed that donepezil 5 mg improves cognition slightly, although the size of the effect is unlikely to be clinically important (mean difference (MD) −0.92 Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) points (range 0 to 70), 95% confidence interval (CI) −1.44 to −0.40; high-certainty evidence). Donepezil 10 mg (MD −2.21 ADAS-Cog points, 95% CI −3.07 to −1.35; moderate-certainty evidence) and galantamine 16 to 24 mg (MD −2.01 ADAS-Cog point, 95%CI −3.18 to −0.85; moderate-certainty evidence) probably also improve cognition, although the larger effect estimates still may not be clinically important. With low certainty, there may be little to no effect of rivastigmine 3 to 12 mg daily on cognition (MD 0.03 ADAS-Cog points, 95% CI −3.04 to 3.10; low-certainty evidence).
Adverse events reported in the studies included nausea and/or vomiting, diarrhoea, dizziness, headache, and hypertension. The results showed that there was probably little to no difference between donepezil 5 mg and placebo in the number of adverse events (odds ratio (OR) 1.22, 95% CI 0.94 to 1.58; moderate-certainty evidence), but there were slightly more adverse events with donepezil 10 mg than with placebo (OR 1.95, 95% CI 1.20 to 3.15; high-certainty evidence). The effect of rivastigmine 3 to 12 mg on adverse events was very uncertain (OR 3.21, 95% CI 0.36 to 28.88; very low-certainty evidence). Galantamine 16 to 24 mg is probably associated with a slight excess of adverse events over placebo (OR 1.57, 95% CI 1.02 to 2.43; moderate-certainty evidence).
In the network meta-analysis (NMA), we included cognition to represent benefit, and adverse events to represent harm. All drugs ranked above placebo for cognition and below placebo for adverse events. We found donepezil 10 mg to rank first in terms of benefit, but third in terms of harms, when considering the network estimates and quality of evidence. Galantamine was ranked second in terms of both benefit and harm. Rivastigmine had the lowest ranking of the cholinesterase inhibitors in both benefit and harm NMA estimates, but this may reflect possibly inadequate doses received by some trial participants and small trial sample sizes.